Abstract There are currently 200,000 hematopoietic cell transplantation (HCT) survivors in the U.S today, a number that will exceed 500,000 by 2030. Despite improvements in overall survival, long-term HCT survivors remain at high risk for chronic health complications such as cardiovascular disease (CVD). Cardiovascular complications, such as myocardial infarction and cardiomyopathy/heart failure, are not only more common in HCT survivors, but they occur earlier than in the general population; in essence, HCT is associated with accelerated cardiovascular aging. However, as highlighted by the recent NIH HCT Late Effects Consensus Conference, the biological mechanisms underlying this problem remain unknown. Our overall hypothesis is that multiple sequential organ system and metabolic impairments sustained prior to, during, or after HCT accelerates depletion of cardiovascular physiologic reserves (cardiovascular reserve capacity), predisposing to early onset CVD. To test this hypothesis, we will measure cardiovascular reserve capacity in a group of HCT survivors over time. Peak oxygen consumption (VO2peak), as derived from cardiopulmonary exercise testing, is the gold standard measure of cardiovascular reserve capacity, because it represents the integrative efficiency with which multiple organ systems deliver and use oxygen for ATP resynthesis. Using a longitudinal study design, we will evaluate VO2peak at baseline (prior to HCT), 6 months, one year and two years post-HCT, allowing us to determine its trajectory over time. We will also determine the impact VO2peak on self-reported physical functioning, and identify populations at high risk for accelerated VO2peak decline after HCT (Aim 1). Importantly, we will use novel diagnostic strategies to define the organic-specific determinants of VO2peak and its impairment after HCT (Aim 2). By the end of our study, we will have: 1) established initial VO2peak in patients undergoing HCT and characterized its post-HCT trajectory over time, identifying patients at highest risk for decline after HCT; 2) informed the screening for subclinical CVD, using strategies that are readily applicable in the clinical setting; and 3) identified mechanisms by which organ-specific impairments, alone and in combination, contribute to abnormalities in VO2peak after HCT. This proposal builds on our previous successful research and will address important knowledge gaps about cardiovascular complications in HCT survivors. Information obtained from this proposal will support development of evidence-based interventions to decrease the risk of CVD after HCT. The growing population of long-term HCT survivors makes development of prevention strategies imperative, to ensure that these survivors live long and healthy lives well after completion of HCT.